Project Summary Diabetes mellitus is a major health concern, affecting over 30 million people in the United States. Serious complications resulting from diabetes including include heart disease, stroke, hypertension, blindness, nervous system damage, and autonomic dysfunction. A major impediment to developing successful diabetes treatments (versus treating symptoms) is the relative knowledge gap regarding the multifaceted and redundant systems that are affected by and contribute to control of metabolic homeostasis. This proposal investigates disease-related plasticity of central neural circuitry controlling autonomic function. Experiments utilize murine models of type 1 and type 2 diabetes. Second-order viscerosensory neurons in the nucleus tractus solitarius (NTS) are glucosensors and contribute significantly to autonomic regulation of glucose homeostasis by signaling integrated visceral and humoral signals to brain areas that directly regulate systemic glucose levels, including the dorsal motor nucleus of the vagus nerve (DMV), which contains vagal motor neurons. Vagal motor function is altered in diabetes, leading to autonomic dysregulation, including excess hepatic glucose production and gastric motility dysfunction. We have found that changes in activity of GABA neurons or altering glucose pathways in the NTS affect systemic [glucose]. Glutamate and GABA receptors are reorganized, and synaptic excitation of NTS GABA neurons is persistently increased in the vagal complex after a few days of hyperglycemia in a model of type 1 diabetes. The majority of GABA neurons in the NTS is responsive to elevated [glucose], being either excited or inhibited, but glucose-excitatory responses are blunted in diabetic mice. Vertical sleeve gastrectomy rapidly improves glycemic index in patients and animal models of diabetes, independent of weight loss; convergent data suggest the brainstem dorsal vagal complex (DVC) is integral to this response. Electrophysiological recordings from NTS neurons in slices, chemogenetic and pharmacological manipulation of NTS neuron activity, and direct glutamate and glucose measurements from the NTS of control and diabetic mice will be used to obtain functional cellular and molecular data relevant to the contribution of the NTS to glucose metabolism in the streptozotocin-treated mouse and the BKS-db mouse, models of type 1 and type 2 diabetes, respectively. The broad hypothesis of this proposal is that altered neural function in the vagal complex reflects a neurogenic component of diabetic pathology. The experiments in this proposal aim to: 1) Identify cellular outcomes of glucose responsiveness in the caudal DVC associated with diabetes; 2); Determine effects of DVC manipulation on systemic glucose metabolism; and 3) Determine effects of bariatric surgery on diabetes-related neuroplasticity in the vagal complex. Results will guide future development of novel disease-modifying therapies, based on modulating specific neural functions in the vagal system to address diabetes-related glycemic dysregulation in patients.